Complexity of lung cancer modifiers: Mapping of thirty genes and twenty-five interactions in half of the mouse genome
Complexity of lung cancer modifiers: Mapping of thirty genes and twenty-five interactions in half of the mouse genome
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DOI：
10.1093/jnci/93.19.1484
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发表时间：
2001-10-03
期刊：
影响因子：
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通讯作者：
Demant, P
中科院分区：
文献类型：
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作者：
Tripodis, N;Hart, AAM;Demant, P
背景：实验动物中有许多低外显率基因控制着癌症易感性，但这组基因的总体遗传信息（即位点数量及其相互作用）尚不清楚。我们进行了系统的搜索，使用小鼠重组同源（RC）菌株扫描了大约一半的小鼠基因组，寻找影响肿瘤大小或数量的肺癌易感性（Slue）基因。在每个RC菌株（OcB）中，大约12.5%的基因组来自肺癌抗性菌株B10。而其余的则来自于肺癌易感菌株O20。方法：对5个（OcB × O20）杂交组合730份F-2杂交材料进行检测。在妊娠第18天给孕鼠注射单剂量n -乙基-n -亚硝基脲。当子代16周龄时，取全肺半切片，并测定所有肺肿瘤的大小（n = 2658）。采用方差分析检测关联，并使用统计程序对模型（包括主效应和双向相互作用）进行检验。结果：我们共检测到30个Sluc位点（16个新位点加上先前报道的14个位点）和25个双向相互作用位点。其中一些相互作用是相互抵消的（如Sluc17和Sluc20），导致每个相关位点的个体独立效应（主效应）部分或全部被掩盖。在一个以上的RC菌株中检测到7个位点（Sluc1、Sluc5、Sluc12、Sluc16、Sluc18、Sluc20和Sluc26）和2个相互作用位点（Sluc5 × Sluc12和Sluc5 × Sluc26）。结论：将我们的结果外推到整个基因组，表明大约有60个Sluc位点（90%置信区间= 42至78）。尽管肺癌的遗传复杂性，使用适当的定位策略可以识别大量的相关基因座，并可以揭示它们的相互作用。这项研究提供了对肺肿瘤发生的遗传控制的见解，并可能作为研究其他癌症类型遗传学的范例。
Background: Numerous low-penetrance genes control susceptibility to cancer in experimental animals, but the overall genetic information on this group of genes (i.e., number of loci and their mutual interactions) is missing. We performed a systematic search, scanning roughly half of the mouse genome for lung cancer susceptibility (Slue) genes affecting tumor size or number by using mouse recombinant congenic (RC) strains. In each RC strain (OcB), approximately 12.5% of the genome is derived from the lung cancer-resistant strain B10.O20, whereas the rest is derived from the lung cancer-susceptible strain O20. Methods: A total of 730 F-2 hybrids from five (OcB x O20) crosses were tested. Pregnant mice were treated on day 18 of gestation with a single dose of N-ethyl-N-nitrosourea. When offspring were 16 weeks old, whole lungs were removed and sectioned semiserially, and the size of all lung tumors (n = 2658) was determined. Analysis of variance was used for detection of linkage, and models (including main effect and two-way interactions) were tested with a statistical program. Results: We detected a total of 30 Sluc loci (16 new plus 14 previously reported) and 25 two-way interactions. Some of these interactions are counteracting (e.g., Sluc17 and Sluc20), resulting in the partial or total masking of the individual independent effect (main effect) of each involved locus. Seven loci (Sluc1, Slue-5, Sluc12, Sluc16, Sluc18, Sluc20, and Sluc26) and two interactions (Sluc5 x Sluc12 and Sluc5 x Sluc26) were detected in more than one RC strain. Conclusions: The extrapolation of our results to the whole genome suggests approximately 60 Sluc loci (90% confidence intervals = 42 to 78). Despite the genetic complexity of lung cancer, use of appropriate map-ping strategies can identify a large number of responsible loci and can reveal their interactions. This study provides an insight into the genetic control of lung tumorigenesis and may serve as a paradigm for investigating the genetics of other cancer types.